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Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones
Published on: February 7, 2019
Synthesis and Stereochemical Assignment of Diastereomeric Steroidal Spiro-1,2,4-trioxolanes with Sitostanone Motif
Alexander Lobov1, Anastasiya Kerimova1, Irina Smirnova1
1Ufa Institute of Chemistry of the Ufa Federal Research Centre of the Russian Academy of Sciences, 71, pr. Oktyabrya, 450054 Ufa, Russia.
Abstract:
The synthesis and multi-step spectroscopic characterization of diastereomeric 3-spiro-1,2,4-trioxolanes obtained by Griesbaum co-ozonolysis of sitostanone O-methyl oxime with two types of fluorinated ketones are reported. The reaction furnished four possible diastereomers that differ in the α/β orientation of the peroxide bridge relative to the steroid A-ring and in the syn/anti orientation of the trifluoromethyl group at C5'. A chemometric PLS2 approach, linking experimental and DFT-calculated 13C chemical shifts, was used for the objective stereochemical assignment of each diastereomer in the inseparable mixtures. Single-crystal X-ray analysis of the isolated 3R,5'R and 3R,5'S stereoisomeric pair (α-anti and α-syn ozonides) provided unambiguous absolute configurations that validated the stereochemical assignments obtained by the combined NMR/DFT/PLS2 approach. This integrated synthetic, crystallographic, spectroscopic, and chemometric methodology provides reliable configurational assignment in complex spiro-peroxide mixtures and expands the analytical toolkit for such systems.
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